Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study

F. Perrier; V. Viallon; S. Ambatipudi; A. Ghantous; C. Cuenin; H. Hernandez-Vargas; V. Chajès; L. Baglietto; M. Matejcic; H. Moreno-Macias; T. Kühn; H. Boeing; A. Karakatsani; A. Kotanidou; A. Trichopoulou; S. Sieri; S. Panico; F. Fasanelli; M. Dolle; C. Onland-Moret; I. Sluijs; E. Weiderpass; J. R. Quirós; A. Agudo; J. M. Huerta; E. Ardanaz; M. Dorronsoro; T. Y.N. Tong; K. Tsilidis; E. Riboli; M. J. Gunter; Z. Herceg; P. Ferrari; I. Romieu

doi:10.1186/s13148-019-0637-x

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study

F. Perrier, V. Viallon, S. Ambatipudi, A. Ghantous, C. Cuenin, H. Hernandez-Vargas, V. Chajès, L. Baglietto, M. Matejcic, H. Moreno-Macias, T. Kühn, H. Boeing, A. Karakatsani, A. Kotanidou, A. Trichopoulou, S. Sieri, S. Panico, F. Fasanelli, M. Dolle, C. Onland-MoretI. Sluijs, E. Weiderpass, J. R. Quirós, A. Agudo, J. M. Huerta, E. Ardanaz, M. Dorronsoro, T. Y.N. Tong, K. Tsilidis, E. Riboli, M. J. Gunter, Z. Herceg, P. Ferrari^*, I. Romieu

^*Corresponding author for this work

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Abstract

Background: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features.

Results: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q _val = 0.029 and q _val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL.

Conclusions: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Original language	English
Article number	57
Number of pages	13
Journal	Clinical Epigenetics
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s13148-019-0637-x
Publication status	Published - 02 Apr 2019
Externally published	Yes

Bibliographical note

Funding Information:
The authors would like to thank the financial support provided by La Fondation de France for a doctoral fellowship. They are also grateful for all the women who participated in the EPIC cohort and without whom this work would not have been possible.

Funding Information:
This work was supported by a doctoral fellowship from ‘Fondation de France’ (grant number 2015 00060737) to FP and the grants from the Institut National du Cancer (INCa, France, 2012-070 to IR and ZH), la Ligue nationale contre le cancer (to Z. Herceg). ZH was supported by the European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework, the Fondation Association pour la Recherche contre le Cancer (ARC, France). In addition, this study was supported by postdoctoral fellowship to SA from the International Agency for Research on Cancer, partially supported by the EC FP7 Marie Curie Actions – People – Co-funding of regional, national and international programmes (COFUND). SA’s work is supported by Cancer Research UK (grant number: C18281/A19169). SA work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (grant number: MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/5). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, PI13/02633 to EPIC-Navarra), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the manuscript.

Publisher Copyright:
© 2019 The Author(s).

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

Alcohol intake
Dietary folate
DMR
DNA methylation
EPIC cohort
Fused lasso

ASJC Scopus subject areas

Molecular Biology
Genetics
Developmental Biology
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Cite this

Perrier, F., Viallon, V., Ambatipudi, S., Ghantous, A., Cuenin, C., Hernandez-Vargas, H., Chajès, V., Baglietto, L., Matejcic, M., Moreno-Macias, H., Kühn, T., Boeing, H., Karakatsani, A., Kotanidou, A., Trichopoulou, A., Sieri, S., Panico, S., Fasanelli, F., Dolle, M., ... Romieu, I. (2019). Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study. Clinical Epigenetics, 11(1), Article 57. https://doi.org/10.1186/s13148-019-0637-x

@article{0fbcfb110bfa409589cd00bb552f0e69,

title = "Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study",

abstract = " Background: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. Results: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q val = 0.029 and q val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. Conclusions: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer. ",

keywords = "Alcohol intake, Dietary folate, DMR, DNA methylation, EPIC cohort, Fused lasso",

author = "F. Perrier and V. Viallon and S. Ambatipudi and A. Ghantous and C. Cuenin and H. Hernandez-Vargas and V. Chaj{\`e}s and L. Baglietto and M. Matejcic and H. Moreno-Macias and T. K{\"u}hn and H. Boeing and A. Karakatsani and A. Kotanidou and A. Trichopoulou and S. Sieri and S. Panico and F. Fasanelli and M. Dolle and C. Onland-Moret and I. Sluijs and E. Weiderpass and Quir{\'o}s, {J. R.} and A. Agudo and Huerta, {J. M.} and E. Ardanaz and M. Dorronsoro and Tong, {T. Y.N.} and K. Tsilidis and E. Riboli and Gunter, {M. J.} and Z. Herceg and P. Ferrari and I. Romieu",

note = "Funding Information: The authors would like to thank the financial support provided by La Fondation de France for a doctoral fellowship. They are also grateful for all the women who participated in the EPIC cohort and without whom this work would not have been possible. Funding Information: This work was supported by a doctoral fellowship from {\textquoteleft}Fondation de France{\textquoteright} (grant number 2015 00060737) to FP and the grants from the Institut National du Cancer (INCa, France, 2012-070 to IR and ZH), la Ligue nationale contre le cancer (to Z. Herceg). ZH was supported by the European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework, the Fondation Association pour la Recherche contre le Cancer (ARC, France). In addition, this study was supported by postdoctoral fellowship to SA from the International Agency for Research on Cancer, partially supported by the EC FP7 Marie Curie Actions – People – Co-funding of regional, national and international programmes (COFUND). SA{\textquoteright}s work is supported by Cancer Research UK (grant number: C18281/A19169). SA work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (grant number: MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/5). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, PI13/02633 to EPIC-Navarra), Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the manuscript. Publisher Copyright: {\textcopyright} 2019 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = apr,

day = "2",

doi = "10.1186/s13148-019-0637-x",

language = "English",

volume = "11",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "Springer Verlag",

number = "1",

}

Perrier, F, Viallon, V, Ambatipudi, S, Ghantous, A, Cuenin, C, Hernandez-Vargas, H, Chajès, V, Baglietto, L, Matejcic, M, Moreno-Macias, H, Kühn, T, Boeing, H, Karakatsani, A, Kotanidou, A, Trichopoulou, A, Sieri, S, Panico, S, Fasanelli, F, Dolle, M, Onland-Moret, C, Sluijs, I, Weiderpass, E, Quirós, JR, Agudo, A, Huerta, JM, Ardanaz, E, Dorronsoro, M, Tong, TYN, Tsilidis, K, Riboli, E, Gunter, MJ, Herceg, Z, Ferrari, P & Romieu, I 2019, 'Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study', Clinical Epigenetics, vol. 11, no. 1, 57. https://doi.org/10.1186/s13148-019-0637-x

TY - JOUR

T1 - Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study

AU - Perrier, F.

AU - Viallon, V.

AU - Ambatipudi, S.

AU - Ghantous, A.

AU - Cuenin, C.

AU - Hernandez-Vargas, H.

AU - Chajès, V.

AU - Baglietto, L.

AU - Matejcic, M.

AU - Moreno-Macias, H.

AU - Kühn, T.

AU - Boeing, H.

AU - Karakatsani, A.

AU - Kotanidou, A.

AU - Trichopoulou, A.

AU - Sieri, S.

AU - Panico, S.

AU - Fasanelli, F.

AU - Dolle, M.

AU - Onland-Moret, C.

AU - Sluijs, I.

AU - Weiderpass, E.

AU - Quirós, J. R.

AU - Agudo, A.

AU - Huerta, J. M.

AU - Ardanaz, E.

AU - Dorronsoro, M.

AU - Tong, T. Y.N.

AU - Tsilidis, K.

AU - Riboli, E.

AU - Gunter, M. J.

AU - Herceg, Z.

AU - Ferrari, P.

AU - Romieu, I.

N1 - Funding Information: The authors would like to thank the financial support provided by La Fondation de France for a doctoral fellowship. They are also grateful for all the women who participated in the EPIC cohort and without whom this work would not have been possible. Funding Information: This work was supported by a doctoral fellowship from ‘Fondation de France’ (grant number 2015 00060737) to FP and the grants from the Institut National du Cancer (INCa, France, 2012-070 to IR and ZH), la Ligue nationale contre le cancer (to Z. Herceg). ZH was supported by the European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework, the Fondation Association pour la Recherche contre le Cancer (ARC, France). In addition, this study was supported by postdoctoral fellowship to SA from the International Agency for Research on Cancer, partially supported by the EC FP7 Marie Curie Actions – People – Co-funding of regional, national and international programmes (COFUND). SA’s work is supported by Cancer Research UK (grant number: C18281/A19169). SA work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (grant number: MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/5). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, PI13/02633 to EPIC-Navarra), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the manuscript. Publisher Copyright: © 2019 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/4/2

Y1 - 2019/4/2

N2 - Background: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. Results: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q val = 0.029 and q val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. Conclusions: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

AB - Background: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. Results: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q val = 0.029 and q val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. Conclusions: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

KW - Alcohol intake

KW - Dietary folate

KW - DMR

KW - DNA methylation

KW - EPIC cohort

KW - Fused lasso

U2 - 10.1186/s13148-019-0637-x

DO - 10.1186/s13148-019-0637-x

M3 - Article

C2 - 30940212

AN - SCOPUS:85063779953

SN - 1868-7075

VL - 11

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 57

ER -

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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